HEPARIN-BINDING PROTEIN LEVELS PREDICT UNFAVORABLE OUTCOME IN COVID-19 PNEUMONIA: A POST HOC ANALYSIS OF THE SAVE TRIAL.

ABSTRACT: We aimed to evaluate heparin-binding protein (HBP) as a marker of prognosis of unfavorable outcome in COVID-19 pneumonia. This was a post hoc analysis of the SAVE clinical trial investigating anakinra treatment, guided by suPAR (soluble urokinase plasminogen activator receptor) levels ≥6 ng/mL, for the prevention of severe respiratory failure in hospitalized patients with COVID-19 pneumonia. Baseline HBP plasma levels were measured in 534 patients by fluorescence dry quantitative immunoassay using the Jet-iStar 800 analyzer. Concentrations higher than 35 ng/mL predicted 30-day mortality with a moderate specificity of 53.3% and negative predictive value 78.1%; sensitivity was low (29.0%). After multivariate Cox analysis, HBP higher than 35 ng/mL was an independent predictor of 30-day unfavorable outcome (adjusted hazard ratio, 1.77; 95% CI, 1.06-2.94; P = 0.028) and these patients were also at greater risk of death after 90 days (hazard ratio, 1.85; 95% CI, 1.25-2.74; P = 0.002). The cutoff was not predictive of development of severe respiratory failure, septic shock or acute kidney injury. Among patients with baseline HBP levels higher than 35 ng/mL, anakinra treatment was associated with decreased mortality (7.2%) versus comparators (18.1%; P < 0.001). Results confirm that HBP may be an early biomarker of poor outcome among preselected patients at risk from COVID-19 pneumonia.ClinicalTrials.gov registration NCT04357366.

Transitions of blood immune endotypes and improved outcome by anakinra in COVID-19 pneumonia: an analysis of the SAVE-MORE randomized controlled trial.

BACKGROUND: Endotype classification may guide immunomodulatory management of patients with bacterial and viral sepsis. We aimed to identify immune endotypes and transitions associated with response to anakinra (human interleukin 1 receptor antagonist) in participants in the SAVE-MORE trial. METHODS: Adult patients hospitalized with radiological findings of PCR-confirmed severe pneumonia caused by SARS-CoV-2 and plasma-soluble urokinase plasminogen activator receptor levels of ≥ 6 ng/ml in the SAVE-MORE trial (NCT04680949) were characterized at baseline and days 4 and 7 of treatment using a previously defined 33-messenger RNA classifier to assign an immunological endotype in blood. Endpoints were changes in endotypes and progression to severe respiratory failure (SRF) associated with anakinra treatment. RESULTS: At baseline, 23.2% of 393 patients were designated as inflammopathic, 41.1% as adaptive, and 35.7% as coagulopathic. Only 23.9% were designated as the same endotype at days 4 and 7 compared to baseline, while all other patients transitioned between endotypes. Anakinra-treated patients were more likely to remain in the adaptive endotype during 7-day treatment (24.4% vs. 9.9%; p < 0.001). Anakinra also protected patients with coagulopathic endotype at day 7 against SRF compared to placebo (27.8% vs. 55.9%; p = 0.013). CONCLUSION: We identify an association between endotypes defined using blood transcriptome and anakinra therapy for COVID-19 pneumonia, with anakinra-treated patients shifting toward endotypes associated with a better outcome, mainly the adaptive endotype. Trial registration ClinicalTrials.gov, NCT04680949, December 23, 2020.

Validation of FIB-6 score in assessment of liver fibrosis in chronic hepatitis B.

BACKGROUND: We recently developed a simple novel index called fibrosis 6 (FIB-6) using machine learning data analysis. We aimed to evaluate its performance in the diagnosis of liver fibrosis and cirrhosis in chronic hepatitis B (CHB). METHODS: A retrospective observational analysis of data was obtained from seven countries (Egypt, Kingdom of Saudi Arabia (KSA), Turkey, Greece, Oman, Qatar, and Jordan) of CHB patients. The inclusion criteria were receiving an adequate liver biopsy and a complete biochemical and hematological data. The diagnostic performance analysis of the FIB-6 index was conducted and compared with other non-invasive scores. RESULTS: A total of 603 patients were included for the analysis; the area under the receiver operating characteristic curve (AUROC) of FIB-6 for the discrimination of patients with cirrhosis (F4), compensated advanced chronic liver disease (cACLD) (F3 and F4), and significant fibrosis (F2-F4) was 0.854, 0.812, and 0.745, respectively. The analysis using the optimal cut-offs of FIB-6 showed a sensitivity of 70.9%, specificity of 84.1%, positive predictive value (PPV) of 40.3%, and negative predictive value (NPV) of 95.0% for the diagnosis of cirrhosis. For the diagnosis of cACLD, the results were 71.5%, 69.3%, 40.8%, and 89.2%, respectively, while for the diagnosis of significant fibrosis, the results were 68.3%, 67.5%, 59.9%, and 75.0%, respectively. When compared to those of fibrosis 4 (FIB-4) index, aspartate aminotransferase (AST)-to-platelet ratio index (APRI), and AST-to-alanine aminotransferase (ALT) ratio (AAR), the AUROC for the performance of FIB-6 was higher than that of FIB-4, APRI, and AAR in all fibrosis stages. FIB-6 gave the highest sensitivity and NPV (89.1% and 92.4%) in ruling out cACLD and cirrhosis, as compared to FIB-4 (63.8% and 83.0%), APRI (53.9% and 86.6%), and AAR (47.5% and 82.3%), respectively. CONCLUSIONS: The FIB-6 index could be used in ruling out cACLD, fibrosis, and cirrhosis with good reliability.

NMR-based metabolomic signature: An important tool for the diagnosis and study of pathogenesis of autoimmune hepatitis.

BACKGROUND AND AIMS: Metabolomics is used to predict, diagnose, and monitor metabolic disorders but altered metabolomic signatures have also been reported in diverse diseases, including autoimmune disorders. However, the metabolomic profile in autoimmune hepatitis (AIH) has not been investigated in depth. Therefore, we investigated the metabolomic signature of AIH and its significance as a diagnostic and pathogenetic tool. APPROACH AND RESULTS: Metabolites in plasma samples from 50 patients with AIH at diagnosis, 43 healthy controls, 72 patients with primary biliary cholangitis (PBC), 26 patients with metabolic dysfunction-associated liver disease, and 101 patients with chronic viral hepatitis were determined by 1 H NMR (nuclear magnetic resonance) spectroscopy. Fifty-two metabolites were quantified, and metabolic pathway analysis was performed. Multivariate analysis revealed that AIH could be differentiated from healthy controls and each of the disease controls ( p <0.001). Fifteen metabolites differentiated AIH from disease controls (PBC+chronic viral hepatitis+metabolic dysfunction-associated liver disease) (95% sensitivity and 92% specificity). Ten distinct metabolic pathways were altered in AIH compared to disease controls. The metabolic pathway of branched-chain amino acids (lower valine, leucine, and isoleucine levels and their catabolic intermediates in PBC), methionine (lower methionine, 2-aminobutyrate, and 2-hydroxybutyrate levels in PBC), alanine-aspartate-glutamate (lower metabolites in PBC), and that of metabolites associated with gut microbiota (lower choline, betaine, and dimethylamine levels in PBC) were significantly different between AIH and PBC ( p <0.01). CONCLUSIONS: 1 H NMR spectroscopy could be a promising novel tool to diagnose and study AIH pathogenesis as there is no need for much sample handling, is highly reproducible with high sensitivity and specificity, and low cost.

Clarithromycin for early anti-inflammatory responses in community-acquired pneumonia in Greece (ACCESS): a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Addition of macrolide antibiotics to ß-lactam antibiotics for the treatment of patients in hospital with community-acquired pneumonia is based on results from observational studies and meta-analyses rather than randomised clinical trials. We investigated if addition of the macrolide clarithromycin to treatment with a ß-lactam antibiotic in this population could improve early clinical response-the new regulatory endpoint for community-acquired pneumonia-and explored the possible contribution of modulation of the inflammatory host response to that outcome. METHODS: The ACCESS trial was a phase 3 prospective, double-blind, randomised controlled trial, in which adults in hospital with community-acquired pneumonia who had systemic inflammatory response syndrome, Sequential Organ Failure Assessment (SOFA) score of 2 or more, and procalcitonin 0·25 ng/mL or more were enrolled in 18 internal medicine departments of public Greek hospitals. Patients were randomly assigned (1:1) by computer-generated block randomisation to standard of care medication (including intravenous administration of a third-generation cephalosporin or intravenous administration of ß-lactam plus ß-lactamase inhibitor combination) plus either oral placebo or oral clarithromycin 500 mg twice daily for 7 days. Investigators, staff, and patients were masked to group allocation. The primary composite endpoint required that patients fulfilled both of the following conditions after 72 hours (ie, day 4 of treatment): (1) decrease in respiratory symptom severity score of 50% or more as an indicator of early clinical response and (2) decrease in SOFA score of at least 30% or favourable procalcitonin kinetics (defined as ≥80% decrease from baseline or procalcitonin <0·25 ng/mL), or both, as an indicator of early inflammatory response. Participants who were randomly assigned and received allocated treatment were included in the primary analysis population. This trial is complete and is registered with the EU Clinical Trials Register (2020-004452-15) and ClinicalTrials.gov (NCT04724044). FINDINGS: Patients were enrolled between Jan 25, 2021, and April 11, 2023, and 278 individuals were randomly allocated to receive standard of care in combination with either clarithromycin (n=139) or placebo (n=139). 134 patients in the clarithromycin group (five withdrew consent) and 133 patients in the placebo group (six withdrew consent) were included in the analysis of the primary endpoint. The primary endpoint was met in 91 (68%) patients in the clarithromycin group and 51 (38%) patients in the placebo group (difference 29·6% [95% CI 17·7-40·3]; odds ratio [OR] 3·40 [95% CI 2·06-5·63]; p<0·0001). Serious treatment-emergent adverse events (TEAEs) occurred in 58 (43%) patients in the clarithromycin group and 70 (53%) patients in the placebo group (difference 9·4% [95% CI -2·6 to 20·9]; OR 0·67 [95% CI 0·42 to 1·11]; p=0·14). None of the serious TEAEs was judged to be related to treatment assignment. INTERPRETATION: Addition of clarithromycin to standard of care enhances early clinical response and attenuates the inflammatory burden of community-acquired pneumonia. The mechanism of benefit is associated with changes in the immune response. These findings suggest the importance of adding clarithromycin to ß-lactams for treatment of patients in hospital with community-acquired pneumonia to achieve early clinical response and early decrease of the inflammatory burden. FUNDING: Hellenic Institute for the Study of Sepsis and Abbott Products Operations.

Osteonecrosis risk after steroids-related treatment of COVID-19 is not negligible: A cross sectional study.

BACKGROUND & AIMS: During the pandemic, steroids use at various dosages and durations for the treatment of COVID-19 patients, especially in hospitalized patients, was a common and effective strategy. However, steroid administration is associated with osteonecrosis as an adverse event. The aim of the study was to examine the prevalence of skeleton osteonecrosis in COVID-19 patients treated with or without steroids. METHODS: Eighty randomly selected hospitalized COVID-19 patients were analyzed, of which 40 were managed with a published protocol including steroids and 40 did not receive steroids. Demographics and laboratory measurements including white blood cells count, C-reactive protein and ferritin were retrieved from the medical records. All patients underwent magnetic resonance imaging of the hips, shoulders, and knees. Subsequently, all patients were clinically examined and Oxford hip score (OHS) and EuroQol- 5 Dimension (EQ-5D-5 L) were documented. RESULTS: Three patients (3/40; 7.5 %) treated with steroids were diagnosed with femoral head osteonecrosis. None of the patients in the non-steroid-treated group developed osteonecrosis. There were no differences between the two groups regarding OHS and EQ-5D-5 L. Patients with osteonecrosis had higher ferritin levels, received higher doses of corticosteroids (median dose 2200 mg), and had longer hospitalization. CONCLUSIONS: COVID-19-related therapy with steroids resulted in lower prevalence of osteonecrosis than that previously recorded in patients with severe acute respiratory syndrome caused by coronavirus-type-1. However, this risk seems not negligible and therefore, high clinical suspicion for early diagnosis is warranted, given the fact that a great proportion of hospitalized patients received steroids during the COVID-19 pandemic.

Lack of complete biochemical response in autoimmune hepatitis leads to adverse outcome: First report of the IAIHG retrospective registry.

BACKGROUND AND AIMS: The International Autoimmune Hepatitis Group retrospective registry (IAIHG-RR) is a web-based platform with subjects enrolled with a clinical diagnosis of autoimmune hepatitis (AIH). As prognostic factor studies with enough power are scarce, this study aimed to ascertain data quality and identify prognostic factors in the IAIHG-RR cohort. METHODS: This retrospective, observational, multicenter study included all patients with a clinical diagnosis of AIH from the IAIHG-RR. The quality assessment consisted of external validation of completeness and consistency for 29 predefined variables. Cox regression was used to identify risk factors for liver-related death and liver transplantation (LT). RESULTS: This analysis included 2559 patients across 7 countries. In 1700 patients, follow-up was available, with a completeness of individual data of 90% (range: 30-100). During a median follow-up period of 10 (range: 0-49) years, there were 229 deaths, of which 116 were liver-related, and 143 patients underwent LT. Non-White ethnicity (HR 4.1 95% CI: 2.3-7.1), cirrhosis (HR 3.5 95% CI: 2.3-5.5), variant syndrome with primary sclerosing cholangitis (PSC) (HR 3.1 95% CI: 1.6-6.2), and lack of complete biochemical response within 6 months (HR 5.7 95% CI: 3.4-9.6) were independent prognostic factors. CONCLUSIONS: The IAIHG-RR represents the world's largest AIH cohort with moderate-to-good data quality and a relevant number of liver-related events. The registry is a suitable platform for patient selection in future studies. Lack of complete biochemical response to treatment, non-White ethnicity, cirrhosis, and PSC-AIH were associated with liver-related death and LT.

HBV DNA and HBsAg Levels at 24 Weeks Off-Treatment Predict Clinical Relapse and HBsAg Loss in HBeAg-Negative Patients Who Discontinued Antiviral Therapy.

BACKGROUND & AIMS: Patients who discontinue nucleo(s)tide analogue therapy are at risk of viral rebound and severe hepatitis flares, necessitating intensive off-treatment follow-up. METHODS: We studied the association between hepatitis B surface antigen (HBsAg) and hepatitis B virus (HBV) DNA levels at off-treatment follow-up week 24 (FU W24), with subsequent clinical relapse, and HBsAg loss in a multicenter cohort of hepatitis B e antigen (HBeAg)-negative patients with chronic hepatitis B who discontinued nucleo(s)tide analogue therapy. RESULTS: We studied 475 patients, 82% Asian, and 55% treated with entecavir. Patients with higher HBV DNA levels at FU W24 had a higher risk of clinical relapse (hazard ratio [HR], 1.576; P < .001) and a lower chance of HBsAg loss (HR, 0.454; P < .001). Similarly, patients with higher HBsAg levels at FU W24 had a higher risk of clinical relapse (HR, 1.579; P < .001) and a lower chance of HBsAg loss (HR, 0.263; P < .001). A combination of both HBsAg <100 IU/mL and HBV DNA <100 IU/mL at FU W24 identified patients with excellent outcomes (9.9% clinical relapse and 58% HBsAg loss at 216 weeks of follow-up). Conversely, relapse rates were high and HBsAg loss rates negligible among patients with both HBsAg >100 IU/mL and HBV DNA >100 IU/mL (P < .001). CONCLUSIONS: Among HBeAg-negative patients with chronic hepatitis B who discontinued antiviral therapy and who did not experience clinical relapse before FU W24, serum levels of HBV DNA and HBsAg at FU W24 can be used to predict subsequent clinical relapse and HBsAg clearance. A combination of HBsAg <100 IU/mL with HBV DNA <100 IU/mL identifies patients with a low risk of relapse and excellent chances of HBsAg loss and could potentially be used as an early surrogate end point for studies aiming at finite therapy in HBV.

PAGE-B incorporating moderate HBV DNA levels predicts risk of HCC among patients entering into HBeAg-positive chronic hepatitis B.

BACKGROUND & AIMS: Recent studies reported that moderate HBV DNA levels are significantly associated with hepatocellular carcinoma (HCC) risk in hepatitis B e antigen (HBeAg)-positive, non-cirrhotic patients with chronic hepatitis B (CHB). We aimed to develop and validate a new risk score to predict HCC development using baseline moderate HBV DNA levels in patients entering into HBeAg-positive CHB from chronic infection. METHODS: This multicenter cohort study recruited 3,585 HBeAg-positive, non-cirrhotic patients who started antiviral treatment with entecavir or tenofovir disoproxil fumarate at phase change into CHB from chronic infection in 23 tertiary university-affiliated hospitals of South Korea (2012-2020). A new HCC risk score (PAGED-B) was developed (training cohort, n = 2,367) based on multivariable Cox models. Internal validation using bootstrap sampling and external validation (validation cohort, n = 1,218) were performed. RESULTS: Sixty (1.7%) patients developed HCC (median follow-up, 5.4 years). In the training cohort, age, gender, platelets, diabetes and moderate HBV DNA levels (5.00-7.99 log10 IU/ml) were independently associated with HCC development; the PAGED-B score (based on these five predictors) showed a time-dependent AUROC of 0.81 for the prediction of HCC development at 5 years. In the validation cohort, the AUROC of PAGED-B was 0.85, significantly higher than for other risk scores (PAGE-B, mPAGE-B, CAMD, and REAL-B). When stratified by the PAGED-B score, the HCC risk was significantly higher in high-risk patients than in low-risk patients (sub-distribution hazard ratio = 8.43 in the training and 11.59 in the validation cohorts, all p <0.001). CONCLUSIONS: The newly established PAGED-B score may enable risk stratification for HCC at the time of transition into HBeAg-positive CHB. IMPACT AND IMPLICATIONS: In this study, we developed and validated a new risk score to predict hepatocellular carcinoma (HCC) development in patients entering into hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) from chronic infection. The newly established PAGED-B score, which included baseline moderate HBV DNA levels (5-8 log10 IU/ml), improved on the predictive performance of prior risk scores. Based on a patient's age, gender, diabetic status, platelet count, and moderate DNA levels (5-8 log10 IU/ml) at the phase change into CHB from chronic infection, the PAGED-B score represents a reliable and easily available risk score to predict HCC development during the first 5 years of antiviral treatment in HBeAg-positive patients entering into CHB. With a scoring range from 0 to 12 points, the PAGED-B score significantly differentiated the 5-year HCC risk: low <7 points and high ≥7 points.

Incidence and predictors of hepatocellular carcinoma in patients with autoimmune hepatitis.

BACKGROUND AND AIMS: Autoimmune hepatitis (AIH) is a rare chronic liver disease of unknown aetiology; the risk of hepatocellular carcinoma (HCC) remains unclear and risk factors are not well-defined. We aimed to investigate the risk of HCC across a multicentre AIH cohort and to identify predictive factors. METHODS: We performed a retrospective, observational, multicentric study of patients included in the International Autoimmune Hepatitis Group Retrospective Registry. The assessed clinical outcomes were HCC development, liver transplantation, and death. Fine and Gray regression analysis stratified by centre was applied to determine the effects of individual covariates; the cumulative incidence of HCC was estimated using the competing risk method with death as a competing risk. RESULTS: A total of 1,428 patients diagnosed with AIH from 1980 to 2020 from 22 eligible centres across Europe and Canada were included, with a median follow-up of 11.1 years (interquartile range 5.2-15.9). Two hundred and ninety-three (20.5%) patients had cirrhosis at diagnosis. During follow-up, 24 patients developed HCC (1.7%), an incidence rate of 1.44 cases/1,000 patient-years; the cumulative incidence of HCC increased over time (0.6% at 5 years, 0.9% at 10 years, 2.7% at 20 years, and 6.6% at 30 years of follow-up). Patients who developed cirrhosis during follow-up had a significantly higher incidence of HCC. The cumulative incidence of HCC was 2.6%, 4.6%, 5.6% and 6.6% at 5, 10, 15, and 20 years after the development of cirrhosis, respectively. Obesity (hazard ratio [HR] 2.94, p = 0.04), cirrhosis (HR 3.17, p = 0.01), and AIH/PSC variant syndrome (HR 5.18, p = 0.007) at baseline were independent risk factors for HCC development. CONCLUSIONS: HCC incidence in AIH is low even after cirrhosis development and is associated with risk factors including obesity, cirrhosis, and AIH/PSC variant syndrome. IMPACT AND IMPLICATIONS: The risk of developing hepatocellular carcinoma (HCC) in individuals with autoimmune hepatitis (AIH) seems to be lower than for other aetiologies of chronic liver disease. Yet, solid data for this specific patient group remain elusive, given that most of the existing evidence comes from small, single-centre studies. In our study, we found that HCC incidence in patients with AIH is low even after the onset of cirrhosis. Additionally, factors such as advanced age, obesity, cirrhosis, alcohol consumption, and the presence of the AIH/PSC variant syndrome at the time of AIH diagnosis are linked to a higher risk of HCC. Based on these findings, there seems to be merit in adopting a specialized HCC monitoring programme for patients with AIH based on their individual risk factors.

Maternal liver-related symptoms during pregnancy in primary sclerosing cholangitis.

Background & Aims: Although worsening liver-related symptoms during pregnancy can occur in primary sclerosing cholangitis (PSC), there are insufficient data to effectively counsel patients on their pre-conception risk and no clear recommendations on monitoring and management during pregnancy. We aimed to describe maternal liver-related symptoms in pregnancy, both before and after PSC diagnosis, and explore factors associated with worsening symptoms and liver-related outcomes. Methods: We conducted a multicentre retrospective observational study of females with PSC and known pregnancy with live birth, via the International PSC Study Group. We included 450 patients from 12 European centres. Data included clinical variables, liver-related symptoms (pruritus and/or cholangitis) during pregnancy, and liver biochemistry. A composite primary endpoint of transplant-free survival from time of PSC diagnosis was used. Results: There were 266 pregnancies in 178 patients following PSC diagnosis. Worsening liver-related symptoms were reported in 66/228 (28.9%) pregnancies; they had a reduced transplant-free survival (p = 0.03), which retained significance on multivariate analysis (hazard ratio 3.02, 95% CI 1.24-7.35; p = 0.02).Abnormal biochemistry and/or liver-related symptoms (pruritus and/or cholangitis) were noted during pregnancy before PSC diagnosis in 21/167 (12.6%) patients. They had a reduced transplant-free survival from pregnancy (p = 0.01), which did not retain significance in a multivariable model (hazard ratio 1.10, 95% CI 0.43-2.85; p = 0.84). Conclusions: Liver-related symptoms are frequently encountered during pregnancies before the diagnosis of PSC, and pregnancy may expose the pre-clinical phase of PSC in some patients. Worsening liver-related symptoms were seen in a third of our cohort with known PSC during pregnancy; and this subgroup had a poorer prognosis, which may be related to more advanced liver disease at time of pregnancy and/or a more severe disease phenotype. Impact and implications: Patients with PSC can develop worsening of their liver-related symptoms during pregnancy; however, risk factors for this and the long-term implications are not known. We identified that there is a significant risk of these symptoms in pregnancy, both before and after PSC has been diagnosed, particularly in patients with elevated alkaline phosphatase. Furthermore, our findings suggest that worsening symptoms during pregnancy may be associated with adverse long-term clinical outcomes of liver transplantation and death in patients with known PSC. This may be related to the presence of more advanced liver disease at time of pregnancy. This information can be used to counsel patients with PSC before conception and identify patients who need close follow-up after delivery.

Developing a Tool for Differentiation Between Bacterial and Viral Respiratory Infections Using Myxovirus Resistance Protein A and C-Reactive Protein.

INTRODUCTION: The aim was to assess the performance of a blood assay combining measurements of MxA (myxovirus resistance protein A) and CRP (C-reactive protein) to differentiate viral from bacterial respiratory infections. METHODS: In a prospective study, MxA and CRP were measured in the blood by the AFIAS panel in adults admitted with respiratory infection. Patients were split into discovery and validation cohorts. Final diagnosis was adjudicated by a panel of experts. Microbiology-confirmed cases comprised the discovery cohort, and infections adjudicated as highly probable viral or bacterial comprised the validation cohort. RESULTS: A total of 537 patients were analyzed: 136 patients were adjudicated with definitive viral infections and 131 patients with definitive bacterial infections. Using logistic regression analysis, an equation was developed to calculate the probability for bacterial infection using the absolute value of MxA and CRP. Calculated probability ≥ 0.5 and/or MxA to CRP ratio less than 2 applied as the diagnostic rule for bacterial infections. This rule provided 91.6% sensitivity and 90.4% negative predictive value for the diagnosis of bacterial infections. This diagnostic sensitivity was confirmed in the validation cohort. A MxA/CRP ratio less than 0.15 was associated with unfavorable outcome. CONCLUSION: The calculation of the probability for bacterial infection using MxA and CRP may efficiently discriminate between viral and bacterial respiratory infections.

Calprotectin serum levels on admission and during follow-up predict severity and outcome of patients with COVID-19: A prospective study.

BACKGROUND & AIMS: Calprotectin reflects neutrophil activation and is increased in various inflammatory conditions including severe COVID-19. However, serial serum calprotectin measurements in COVID-19 patients are limited. We assessed prospectively, calprotectin levels as biomarker of severity/outcome of the disease and a COVID-19 monitoring parameter in a large cohort of consecutive COVID-19 patients. METHODS: Calprotectin serum levels were measured in 736 patients (58.2 % males; median age 63-years; moderate disease, n = 292; severe, n = 444, intubated and/or died, n = 50). Patients were treated with combined immunotherapies according to our published local algorithm. The endpoint was the composite event of intubation due to severe respiratory failure (SRF)/COVID-19-related mortality. RESULTS: Median (interquartile range) calprotectin levels were significantly higher in patients with severe disease [7(8.2) vs. 6.1(8.1)µg/mL, p = 0.015]. Calprotectin on admission was the only independent risk factor for intubation/death (HR=1.473, 95 %CI=1.003-2.165, p = 0.048) even after adjustment for age, sex, body mass index, comorbidities, neutrophils, lymphocytes, neutrophil to lymphocytes ratio, ferritin, and CRP. The area under the curve (AUC, 95 %CI) of calprotectin for prediction of intubation/death was 0.619 (0.531-0.708), with an optimal cut-off at 13 µg/mL (sensitivity: 44 %, specificity: 79 %, positive and negative predictive values: 13 % and 95 %, respectively). For intubated/died patients, paired comparisons from baseline to middle of hospitalization and subsequently to intubation/death showed significant increase of calprotectin (p = 0.009 and p < 0.001, respectively). Calprotectin alteration had the higher predictive ability for intubation/death [AUC (95 %CI):0.803 (0.664-0.943), p < 0.001]. CONCLUSIONS: Calprotectin levels on admission and their subsequent dynamic alterations could serve as indicator of COVID-19 severity and predict the occurrence of SRF and mortality.

FibroMeter scores are predictive noninvasive markers of advanced and significant liver fibrosis in patients with chronic viral hepatitis or metabolic dysfunction-associated steatotic liver disease.

Background: FibroMeter and FibroMeter vibration-controlled transient elastography (FibroMeter VCTE) were assessed in a Greek cohort of patients with chronic viral hepatitis (CVH) B and C or metabolic dysfunction-associated steatotic liver disease (MASLD) to evaluate their accuracy in predicting advanced liver fibrosis against other well-validated noninvasive markers. Methods: Group 1: n=83 CVH and group 2: n=38 MASLD patients underwent liver biopsy and transient elastography (TE) on the same day as sera collection. FibroMeter scores APRI and FIB-4 were calculated in all 121 patients, while MASLD fibrosis score (MFS) was also calculated in group 2. Results: In CVH, FibroMeter VCTE performed equivalently to TE and better than the other markers in predicting advanced (≥F3) and significant (≥F2) fibrosis (area under the receiver operating characteristic curve [AUC] 0.887, P<0.001 for F3; AUC 0.766 P<0.001 for F2). FibroMeter Virus (cutoff 0.61) had lower sensitivity (20%) but performed equivalently to APRI and FIB-4. In MASLD, all markers but APRI performed equivalently in predicting advanced fibrosis. FibroMeter VCTE >0.2154 had the same sensitivity (100%) and specificity (81%) as TE (cutoff >7.1 kPa). FibroMeter MASLD >0.25 performed equivalently to MFS and FIB4, but with higher specificity (100%). Both FibroMeter and FibroMeter VCTE correlated with liver histology but not with liver enzymes. Conclusions: FibroMeter VCTE predicts accurately advanced fibrosis in CVH and MASLD, irrespectively of transaminase levels. FibroMeter Virus can be applied only as an alternative marker in CVH, while FibroMeter MASLD performs equally to TE and calculated scores (MFS, FIB-4) in predicting advanced fibrosis in MASLD patients.

Multicenter validation of FIB-6 as a novel machine learning non-invasive score to rule out liver cirrhosis in biopsy-proven MAFLD.

BACKGROUND AND AIMS: We previously developed and validated a non-invasive diagnostic index based on routine laboratory parameters for predicting the stage of hepatic fibrosis in patients with chronic hepatitis C (CHC) called FIB-6 through machine learning with random forests algorithm using retrospective data of 7238 biopsy-proven CHC patients. Our aim is to validate this novel score in patients with metabolic dysfunction-associated fatty liver disease (MAFLD). METHOD: Performance of the new score was externally validated in cohorts from one site in Egypt (n = 674) and in 5 different countries (n = 1798) in Iran, KSA, Greece, Turkey and Oman. Experienced pathologists using METAVIR scoring system scored the biopsy samples. Results were compared with FIB-4, APRI, and AAR. RESULTS: A total of 2472 and their liver biopsy results were included, using the optimal cutoffs of FIB-6 indicated a reliable performance in diagnosing cirrhosis, severe fibrosis, and significant fibrosis with sensitivity = 70.5%, specificity = 62.9%. PPV = 15.0% and NPV = 95.8% for diagnosis of cirrhosis. For diagnosis of severe fibrosis (F3 and F4), the results were 86.5%, 24.0%, 15.1% and 91.9% respectively, while for diagnosis of significant fibrosis (F2, F3 and F4), the results were 87.0%, 16.4%, 24.8% and 80.0%). Comparing the results of FIB-6 rule-out cutoffs with those of FIB-4, APRI, and AAR, FIB-6 had the highest sensitivity and NPV (97.0% and 94.7%), as compared to FIB-4 (71.6% and 94.7%), APRI (36.4% and 90.7%), and AAR (61.2% and 90.9%). CONCLUSION: FIB-6 score is an accurate, simple, NIT for ruling out advanced fibrosis and liver cirrhosis in patients with MAFLD.

Radiologic Features of T10 Paravertebral Muscle Sarcopenia: Prognostic Factors in COVID-19.

Background: Sarcopenia, defined as a small cross-sectional area (CSA) in computed tomography (CT) measurements of skeletal muscles, serves as a disease severity marker in various clinical scenarios, including pulmonary conditions and critical illness. Another parameter of sarcopenia, the level of myosteatosis, reflected by the tissue's radiodensity, in the thoracic skeletal muscles group, has been linked to disease progression in coronavirus disease 2019 (COVID-19) patients. We hypothesize that CT-derived measurements of the skeletal muscle density (SMD) and the CSA of thoracic skeletal muscles can predict outcomes in COVID-19 pneumonia. Methods: We retrospectively reviewed the CT scans of 84 patients with COVID-19 pneumonia admitted to two of Greece's largest academic teaching hospitals between April 2020 and February 2021. CSA and SMD at the level of the T10 vertebra were measured using computational imaging methods. The patient population was stratified according to survival status and CT severity score (CT-SS). Correlations were drawn between the radiologic features of sarcopenia, CT severity subgroups, serum inflammatory markers, and adverse events, e.g., death and intubation. Results: Thoracic muscles' CSA measurements correlate with CT-SS and prominent inflammatory markers, such as white blood cell (WBC), C-reactive protein (CRP), fibrinogen, and D-dimers. Moreover, according to linear regression analysis, CSA seems to predict CT-SS variation significantly (ß = -0.266, P = 0.018). CSA proved to differ significantly across survivors (P = 0.027) but not between CT severity categories and intubation subgroups. The AUC (area under the curve) of the receiver operating characteristic (ROC) curve for the predictive value of thoracic muscles' CSA in mortality is 0.774 (95% confidence interval (CI): 0.66 - 0.83, P < 0.000). The optimal cut-off value (Youden index = 0.57) for mortality prognosis, with a sensitivity of 66.7% and a specificity of 88.9%, is 15.55. Thoracic muscles' SMD analyses did not reveal any significant correlations. Conclusions: Easy to obtain and accurately calculated, radiologic features can provide a reliable alternative to laboratory methods for predicting survival in COVID-19. Thoracic muscles' CSA measurement in the level of the T10 vertebra, an acclaimed prognostic imaging assessment that relates directly to CT-SS and inflammatory markers in COVID-19 pneumonia, is a fairly specific tool for survival prognosis.

Treatment responses and outcomes in patients with autoimmune hepatitis and concomitant features of non-alcoholic fatty liver disease.

Background & Aims: Non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) affect 17-46% of Western countries, making coexistence with other liver diseases inevitable. We investigated the prevalence and clinical significance of NAFLD/NASH or the components of metabolic syndrome (MetS) in a large multicentric cohort of patients with autoimmune hepatitis (AIH). Methods: Data from six academic centres (Greece, Canada, Japan, Germany, The Netherlands, and Spain) were evaluated. The presence of NAFLD/NASH in liver biopsy, MetS components, and clinical and laboratory parameters were recorded. Results: A total of 640 patients (474 females, age 49 [4-87] years; follow-up 78 [1-521] months) were included. NAFLD was present in 146 (22.8%) patients (AIH/non-alcoholic fatty liver [NAFL] 115 [18%], AIH/NASH 31 [4.8%]). AIH/NAFL patients were older (p = 0.017), more frequently overweight or obese (p = 0.002), had hypertension (p = 0.001), and had diabetes (p = 0.016), whereas they less frequently had acute presentation (p = 0.002) and soluble liver antigen/liver pancreas positivity (p <0.05), lower transaminases (p <0.001), ALP (p = 0.028) and IgG (p = 0.004) and higher albumin (p <0.001) than patients with AIH only. Patients with AIH/NASH more frequently had cirrhosis at diagnosis (p = 0.036) and higher IgG (p = 0.009). Response to treatment did not differ between groups. Patients with cirrhosis with AIH/NAFL had higher frequency of decompensation compared with patients with AIH only (p <0.05). Patients with type 2 diabetes mellitus and dyslipidaemia had increased hazard of disease progression (p <0.05 for each). Conclusions: The prevalence of NAFLD in AIH is similar to the general population. Concurrence of NASH in patients with AIH signifies a more severe disease, whereas that of NAFL may indicate a worse prognosis in patients with cirrhosis. T2DM and dyslipidaemia in AIH patients are associated with dismal parameters of outcome. Our findings suggest that NAFLD presence or even components of MetS in patients with AIH may affect prognosis, so closer follow-up of such patients is warranted. Impact and implications: Non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) affect many people, making coexistence with other liver diseases inevitable. We investigated the prevalence and clinical significance of NAFLD/NASH or the components of metabolic syndrome (MetS) in patients with autoimmune hepatitis (AIH). NAFLD and NASH presence in patients with AIH is as frequent as in the general population. The concurrence of NASH in patients with AIH seems to signify a more severe disease, whereas that of non-alcoholic fatty liver may indicate a worse prognosis in a specific subgroup of patients who already have cirrhosis at diagnosis. Diabetes or dyslipidaemia in patients with AIH were associated with worse prognosis. Therefore, it seems that closer follow-up of patients with concurrent AIH and NAFLD or AIH and components of MetS is needed.

Lower pretreatment HBV DNA levels are associated with better off-treatment outcomes after nucleo(s)tide analogue withdrawal in patients with HBeAg-negative chronic hepatitis B: A multicentre cohort study.

Background & Aims: Pretreatment predictors of finite nucleo(s)tide analogue (NUC) therapy remain elusive. We studied the association between pretreatment HBV DNA levels and outcomes after therapy cessation. Methods: Patients with chronic hepatitis B who were HBeAg negative at the start of NUC treatment were enrolled from sites in Asia and Europe. We studied the association between pretreatment HBV DNA levels and (1) clinical relapse (defined as HBV DNA >2,000 IU/ml + alanine aminotransferase >2 × the upper limit of normal or retreatment) and (2) HBsAg loss after NUC withdrawal. Results: We enrolled 757 patients, 88% Asian, 57% treated with entecavir, with a median duration of treatment of 159 (IQR 156-262) weeks. Mean pretreatment HBV DNA levels were 5.70 (SD 1.5) log IU/ml and were low (<20,000 IU/ml) in 150 (20%) and high (>20,000 IU/ml) in 607 (80%). The cumulative risk of clinical relapse at 144 weeks after therapy cessation was 22% among patients with pretreatment HBV DNA levels <20,000 IU/ml vs. 60% among patients with pretreatment HBV DNA levels >20,000 IU/ml, whereas the cumulative probabilities of HBsAg loss were 17.5% vs. 5% (p <0.001). In multivariable analysis, pretreatment HBV DNA levels <20,000 IU/ml were independently associated with a reduced likelihood of clinical relapse (adjusted hazard ratio 0.379, p <0.001) and with an increased chance of HBsAg loss (adjusted hazard ratio 2.872, p <0.001). Conclusions: Lower pretreatment HBV DNA levels are associated with a lower risk of clinical relapse and a higher chance of HBsAg loss after cessation of NUC therapy, independent of end-of-treatment viral antigen levels. Further studies are needed to confirm these findings in non-Asian populations. Impact and Implications: A subgroup of patients with chronic hepatitis B may not require retreatment after stopping antiviral therapy. In this study, comprising 757 patients with chronic hepatitis B from Europe and Asia, we found that higher viral load before initiation of treatment was a risk factor for relapse after stopping treatment. Patients with a low HBV DNA level before starting antiviral therapy had the lowest risk of relapse, and a high chance of HBsAg loss, after stopping treatment. These findings can help select patients for treatment withdrawal and guide intensity of off-treatment monitoring.